Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat

Ribeiro, Miriam O.; Lebrun, Fabiana L. A. S.; Christoffolete, Marcelo A.; Branco, Maria dos Remédios Freitas Carvalho; Crescenzi, Alessandra; Carvalho, Suzy D.; Negrão, Núbio; Bianco, Antonio C.

doi:10.1152/ajpendo.2000.279.2.e314

Cited by 50 publications

(47 citation statements)

References 41 publications

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“…Interscapular BAT pad thermal response and NE turnover. The interscapular (IBAT) thermal response to NE was performed as described (16,19) in mice anesthetized with urethane (1.2 g/kg i.p.). Raw data were plotted over time and expressed in terms of maximum ⌬IBAT temperature (°C).…”

Section: Methodsmentioning

confidence: 99%

“…For testing the role of lipogenesis in BAT thermogenesis, this was assessed directly in MEDICA-16 -fed normal mice by measuring changes in the IBAT temperature during infusion of NE in anesthetized mice, as described (19). Because the unstimulated BAT contains a substantial TG depot, all animals were first exposed to cold during 12 h to deplete the brown adipocytes of multilocular fat depots (Fig.…”

Section: Exaggerated Sympathetic Responsiveness In Cold-exposed Hypotmentioning

confidence: 99%

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Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis

et al. 2004

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The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3,5-triiodothyronine (T3), the disruption of which (Dio2 ؊/؊ ) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2 ؊/؊ BAT sympathetic stimulation ϳ10-fold (normal ϳ4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor ␥ coactivator 1, increased well above the levels detected in the coldexposed wild-type animals. The sustained Dio2 ؊/؊ BAT adrenergic hyperresponse suppressed the three-to fourfold stimulation of BAT lipogenesis normally seen after 24 -48 h in the cold. Pharmacological suppression of lipogenesis with ␤␤-methyl-substituted ␣--dicarboxylic acids of C14 -C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2 ؊/؊ mice. A dequate quantities of thyroid hormone are required for the maintenance of basal energy expenditure (1,2) and are also critical for adjustments in energy homeostasis during acute exposure to cold, without which survival is not possible (3). These adjustments in nonshivering adaptive thermogenesis are initiated by an increase in the activity of the sympathetic nervous system (SNS). In human newborns and other small mammals, brown adipose tissue (BAT) is the main site of the sympathetic-mediated adaptive thermogenesis. During cold exposure, there is an acute ϳ50-fold increase in type 2 iodothyronine deiodinase (D2) activity in BAT that accelerates thyroxine (T4) to 3,3Ј,5-triiodothyronine (T3) conversion (4). This increases thyroid hormone receptor (TR) saturation and leads to intracellular thyrotoxicosis specifically in this tissue (5), which in turn increases adrenergic responsiveness (6 -8) in a feed-forward mechanism that allows BAT to produce heat in a sustainable manner.The current paradigm of thyroid-adrenergic synergism is based on the principle that hypothyroidism causes a generalized decrease in adrenergic responsiveness and, therefore, frustrates the homeostatic role of the SNS, including the stimulation of BAT (9,10). However, these studies are largely based on the hypothyroid animal as a model, which has serious limitations for this purpose. The reduced obligatory energy expenditure caused by systemic hypothyroidism leads to a generalized and gradual increase in sympathetic activity that, in the BAT, activates adaptive energy expenditure to sustain normal core temperature, even at room temperature (11). However, chronic norepi...

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Section: Methodsmentioning

confidence: 99%

Section: Exaggerated Sympathetic Responsiveness In Cold-exposed Hypotmentioning

confidence: 99%

Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis

et al. 2004

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“…Thus, the ultimate assessment of BAT thermogenesis should include measurement of BAT temperature in response to adrenergic stimulation. This can be obtained by measuring the thermal response of iBAT to stimulation with an adrenergic agonist (e.g., norepinephrine) in a dose-and time-dependent fashion (627). The setup includes surgical placement of a small thermistor under the iBAT (Fig.…”

Section: And Recommendation 56amentioning

confidence: 99%

“…This setup allows for direct assessment of the thyroid hormone effects in the BAT, bypassing indirect effects. For example, the hypothyroid iBAT is only minimally responsive to an infusion with norepinephrine (627,629).…”

Section: And Recommendation 56amentioning

confidence: 99%

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

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“…Specifically expressed in brown and beige/bright adipocytes, UCP1 is required to mediate adaptive thermogenesis [3][4][5] . Nevertheless, UCP1-independent processes exist to regulate energy expenditure [6][7][8] .…”

mentioning

confidence: 99%

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

Huang

Ruan

et al. 2014

Nat Commun

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Cell growth is tightly coupled with mitochondrial biogenesis in order to maintain energy and organelle homeostasis. Receptor tyrosine kinase Kit and its ligand, stem cell factor (SCF), play a critical role in the growth and survival of multiple cell lineages. Here we report that the expression of SCF and Kit in adipose tissues is responsive to food availability and environmental temperature, and is altered in obese mice and human patients. Mice carrying a lossof-function mutation in Kit develop obesity as a result of decreased energy expenditure. These phenotypes are associated with reduced PGC-1a expression and mitochondrial dysfunction in brown adipose tissue and skeletal muscle. We further demonstrate that SCF/Kit directly promotes Ppargc1a transcription and mitochondrial biogenesis. Blocking Kit signalling in mice decreases PGC-1a expression and thermogenesis, while overexpressing SCF systemically or specifically in brown adipose tissue increases thermogenesis and reduces weight gain. Collectively, these data provide mechanistic insight into the regulation of mitochondrial function by SCF/Kit signalling and lay a foundation for exploring SCF/Kit signalling as a therapeutic target for metabolic diseases.

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Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat

Abstract: 1) hypothyroidism is associated with a blunted IBF thermal response to NE; 2) two- to fourfold changes in mitochondrial UCP1 concentration are not necessarily translated into heat production during NE infusion.

Cited by 50 publications

References 41 publications

Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis

Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

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